Opidol prolonged release tablet ENG

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					SUMMARY OF PRODUCT CHARACTERISTICS


1     NAME OF THE MEDICINAL PRODUCT

      Opidol 100 mg prolonged-release tablets
      Opidol 150 mg prolonged-release tablets
      Opidol 200 mg prolonged-release tablets


2     QUALITATIVE AND QUANTITATIVE COMPOSITION

      Each prolonged-release tablet contains 100 mg of tramadol hydrochloride.
      Each prolonged-release tablet contains 150 mg of tramadol hydrochloride.
      Each prolonged-release tablet contains 200 mg of tramadol hydrochloride.


      For a full list of excipients, see section 6.1.


3     PHARMACEUTICAL FORM
      Prolonged-release tablet

      Opidol 100 mg tablets are off-white, round, biconvex tablets, 9.0 mm in diameter
      Opidol 150 mg tablets are off-white, capsule-shaped tablets, 14.0 mm in length
      Opidol 200 mg tablets are off-white, capsule-shaped tablets, 17.5 mm in length



4     CLINICAL PARTICULARS


4.1   Therapeutic indications

      Treatment of moderate to severe pain.

4.2   Posology and method of administration
      The dose should be adjusted to the severity of the pain and the individual clinical
      response of the patient.

      Adults and adolescents 12 years and older:
      The usual initial dose is one 100 mg Prolonged-release Tablet, twice daily, in the
      morning and evening. The dosage interval must not be less than 8 hours.

      If the pain relief is insufficient, the dose may be increased to:
            one 150 mg prolonged-release tablet, twice daily or
            one 200 mg prolonged-release tablet, twice daily.

      The recommended doses are intended as a guideline.
      Opidol prolonged-release tablets should be swallowed whole without breaking or
      chewing, with a sufficient amount of liquid. The tablets can be taken with or without
      food.

      The dose used should be the lowest dose that provides pain relief. Daily doses of 400
      mg active substance should not be exceeded, except in special clinical circumstances.

      Under no circumstances should Opidol prolonged-release tablets be used for longer
      than absolutely necessary.

      If long-term pain treatment with tramadol is necessary in view of the nature and
      severity of the illness, then careful and regular monitoring should be carried out (if
      necessary with breaks in treatment) to establish whether, and to what extent, further
      treatment is necessary.

      Children:
      Opidol prolonged-release tablets are not suitable for children under the age of 12
      years.

      Elderly:
      A dose adjustment is not usually necessary in elderly patients (up to 75 years) without
      clinically manifest hepatic or renal insufficiency. In elderly patients (over 75 years)
      elimination may be prolonged. Therefore, if necessary, the dosage interval is to be
      extended according to the patients requirements.

      Renal impairment, dialysis and hepatic impairment:
      In patients with serious renal or hepatic impairment the use of Opidol tablets are not
      recommended. In moderate cases, a prolongation of the dosage interval may be
      considered since elimination is delayed.

4.3   Contraindications
      Opidol prolonged-release tablets must not be used in:
             hypersensitivity to tramadol, or any excipients in the tablet (see section 6.1),
             in acute intoxication with alcohol, hypnotics, analgesics, opioids or
             psychotropic medicinal products.
             in patients receiving MAO-inhibitors (such as moclobemide), or within
              2weeks of their withdrawal.
             in patients who are suffering from inadequately controlled epilepsy
      Opidol prolonged-release tablets must not be used for narcotic withdrawal treatment.

4.4   Special warnings and precautions for use

      Opidol prolonged-release tablets must be used with caution in patients dependent on
      opioids (for example, morphine, diamorphine and codeine) , patients suffering head
      injuries, shock, decreased level of consciousness of unknown origin, disturbances of
      the respiratory centre or function, or increased intracranial pressure.


      In patients sensitive for opioids the medicinal product should be used cautiously.
      Convulsions have been reported at recommended dose levels and the risk may be
      increased at doses exceeding the usual upper daily dose limit (400 mg).


      The risk of convulsions may increase in patients taking tramadol and concomitant
      medicinal products that can lower the seizure threshold (see section 4.5. ). Patients
      with a history of epilepsy or those susceptible to seizures should only be treated with
      tramadol if there are compelling reasons.


      Tramadol has a low dependence potential. On long-term use tolerance, psychological
      and physical dependence may develop.


      Reports of dependence and abuse have been less frequent. Because of this potential
      the clinical need for continued analgesic treatment should be reviewed regularly. In
      patients with a tendency to drug abuse or dependence, treatment should be for short
      periods under strict medical supervision.


      Tramadol is not a suitable substitute in opioid dependent patients. The medicinal
      product does not suppress morphine withdrawal symptoms although it is an opioid
      agonist.

4.5   Interaction with other medicinal products and other forms of interaction

      Opidol prolonged-release tablets must not be combined with mono amino oxidase
      (MAO) inhibitors (see section 4.3). Patients taking MAO inhibitors within 14 days
      prior to administration of the opioid pethidine have experienced life-threatening
      interactions that affect the central nervous system and respiratory and cardiovascular
      function. It is possible that tramadol hydrochloride may cause similar interactions
      with MAO inhibitors.


      Concomitant use of Opidol prolonged-release tablets with other centrally acting
      active substances, including alcohol, may potentiate the central nervous system
      effects (see section 4.8).


      The results of pharmacokinetic studies have so far shown that on the concomitant or
      previous administration of cimetidine (enzyme inhibitor) clinically relevant
      interactions are unlikely to occur.


      Simultaneous or previous administration of carbamazepine (enzyme inducer) may
      reduce the analgesic effect and shorten the duration of action.


      In a limited number of pre-and postoperative studies, administration of the antiemetic
      5-HT3 antagonist ondansetron increased the need of tramadol in patients with
      postoperative pain.
      The combination of mixed agonists/antagonists (e.g. buprenorphine, nalbuphine,
      pentazocine) and tramadol is not recommended because it is theoretically possible
      that the analgesic effect of a pure agonist is attenuated under these circumstances.


      Tramadol may induce convulsions and may increase the potential for selective
      serotonin re-uptake inhibitors, tricyclic antidepressants, anti-psychotics and other
      seizure threshold lowering active substances to cause convulsions.


      Isolated cases of serotonergic syndrome have been reported with the therapeutic use
      of tramadol in combination with other serotonergic agents such as selective serotonin
      re-uptake inhibitors (SSRIs).


      Serotonergic syndrome can be manifested by symptoms such as confusion,
      restlessness, fever, sweating, ataxia, hyperreflexia, myoclonia and diarrhoea.
      Withdrawal of the serotonergic agent usually produces a rapid improvement.
      Medicinal treatment depends on the nature and severity of symptoms.


      Caution must be exercised during concomitant treatment with tramadol and coumarin
      derivatives (e.g. warfarin) due to reports of increased international normalisation ratio
      (INR) and ecchymoses in some patients.


      Other medicinal products with a known inhibiting effect on CYP3A4, such as
      ketoconazole, ritonavir and erythromycin, could inhibit the metabolism of tramadol
      (N-demethylation) and probably also the metabolism of the active O-demethyled
      metabolite. The clinical relevancy of this interaction has not been investigated. (See
      4.8 Undesirable effects).



4.6   Fertility, pregnancy and lactation

      Animal tests with very large concentrations of tramadol showed effects on the
      development of the organs, bone formation and mortality of the neonate.


      Teratogenic effects have not been found. Tramadol crosses the placenta.


      Insufficient data are available to assess the safety of tramadol in pregnancy. Therefore
      Opidol prolonged-release tablets must not be used during pregnancy.


      Tramadol – administered before or during birth – does not affect uterine contractility.
      In neonates it may induce changes in the respiratory rate which are usually not
      clinically relevant.
      When breastfeeding about 0.1 % of the maternal tramadol dose is excreted in milk.
      Administration of Opidol prolonged-release tablets is not advised while
      breastfeeding.


      In case of a single administration of tramadol it is not usually required to interrupt
      breastfeeding.



4.7   Effects on ability to drive and use machines

      Opidol prolonged-release tablets may cause dizziness and/or drowsiness and
      therefore, even when used according the directions, can influence the ability to drive
      and use machines. This effect may be potentiated by alcohol, at the beginning of
      treatment, when switching the active substance, and on concomitant use of other
      CNS-depressant or anti-histamines. If patients are affected they should be warned not
      to drive or operate machinery.



4.8   Undesirable effects

      The most commonly reported adverse drug reactions are nausea and dizziness, both
      occurring in more than 10% of patients.


      Immune system disorders
      Rare (>1/10000, <1/1000): Allergic reactions (e.g. dyspnoea, bronchospasm,
      wheezing, angioneurotic oedema) and anaphylaxis


      Metabolism and nutrition disorders
      Rare (>1/10000, < 1/1000): changes in appetite


      Psychiatric disorders
      Rare (>1/10000, <1/1000): hallucinations, anxiety, confusion, sleep disturbances and
      nightmares.
      Psychiatric undesirable effects may vary individually in intensity and nature
      (depending on personality and duration of medication). These include changes in
      mood (usually elation, occasionally dysphoria), changes in activity (usually
      suppression, occasionally increase) and changes in cognitive and sensorial capacity
      (e.g. decision behaviour, perception disorders). Tramadol can cause dependence.
      Symptoms of withdrawal reactions, similar to those occurring during opiate
      withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia,
      hyperkinesias, tremor and gastrointestinal symptoms.


      Nervous system disorders
      Very common (> 1/10): dizziness
Common (>1/100, <1/10): headache, drowsiness
Rare (>1/10000, < 1/1000): paraesthesia, tremor, epileptiform convulsions.
Very rare (< 1/10000): vertigo
Epileptiform convulsions occurred mainly after administration of high doses of
tramadol or after concomitant treatment with active substances which can lower the
seizure threshold or themselves induce cerebral convulsions (see section 4.4 and 4.5).


Eye disorders
Rare (>1/10000, <1/1000): blurred vision


Cardiac disorders
Uncommon (>1/1000, <1/100 ): effects on cardiovascular regulation (palpitation,
tachycardia). These adverse reactions may occur especially on intravenous
administration and in patients who are physically stressed.
Rare (>1/10000, <1/1,000): bradycardia


Vascular disorders
Uncommon (>1/1000, <1/100): postural hypotension or cardiovascular collapse
Rare (>1/10000, <1/1,000): increase in blood pressure.
Very rare (<1/10000): flushing


Respiratory, thoracic and mediastinal disorders
Worsening of asthma has also been reported, though a causal relationship has not
been established.
Rare (>1/10000, <1/1000):: Dyspnoea, respiratory depression
If the recommended doses are considerably exceeded and other centrally depressant
active substances are administered concomitantly (see section 4.5 "Interaction with
other medicinal products and other forms of interaction") respiratory depression may
occur.


Gastrointestinal disorders
Very common (>1/10): vomiting, nausea
Common (>1/100, <1/10): constipation, dry mouth.
Uncommon (>1/1000, <1/100): Retching, gastrointestinal irritation (a feeling of
pressure in the stomach, bloating, diarrhoea).


Hepato-biliary disorders
Very rare (<1/10000), including isolated reports of an increase in liver enzyme values
has been reported after use of tramadol.
      Skin and subcutaneous tissue disorders
      Common (>1/100, <1/10): sweating
      Uncommon (>1/1,000, <1/100): dermal reactions (e.g. pruritus, rash, urticaria)


      Musculoskeletal, connective tissue and bone disorders
      Rare (>1/10000, <1/1000): motorial weakness


      Renal and urinary disorders
      Rare (>1/10000, <1/1000): micturition disorders (difficulty in passing urine and
      urinary retention).


      General disorders
      Common (>1/100, <1/10): fatigue


      Withdrawal symptoms, similar to those that occur in association with opiate
      withdrawal, may manifest as follows: agitation, anxiety, nervousness, insomnia,
      hyperkinesia, tremor and gastrointestinal disturbances. Other symptoms which have
      rarely been observed in connection with the discontinuation of tramadol treatment
      include: panic attacks, severe anxiety, hallucinations, paresthesia, tinnitus and
      unusual CNS symptoms.



4.9   Overdose

      Symptoms:
      In tramadol intoxication, in principle, the same symptoms occur as for all other
      centrally acting analgesics (opioids). In particular, these include miosis, vomiting,
      cardiovascular collapse, depression of consciousness leading to coma, convulsions,
      respiratory depression leading to respiratory failure.


      Treatment:
      General emergency measures are applicable.


      These include protection of the airway, maintenance of respiration and cardiovascular
      circulation depending on the symptoms. In addition activated charcoal can be
      considered. The antidote for respiratory depression is naloxone.


      In animal tests naloxone proved to be ineffective against convulsions. In that case
      diazepam should be administered intravenously.
      Tramadol is only minimally removed from plasma using haemodialysis or
      haemofiltration. Therefore treatment of acute overdose of tramadol using
      haemodialysis or haemofiltration alone is not a suitable way of detoxification.



5     PHARMACOLOGICAL PROPERTIES


5.1   Pharmacodynamic properties

      Pharmacotherapeutic group: Analgesics, other opioids
      ATC code: N02AX02


      Tramadol is a centrally acting opioid analgesic.
      It is a non-selective, complete agonist of μ-, δ- and κ- opioid receptors with a higher
      affinity for μ-receptors. Other mechanisms contributing to the analgesic effect are the
      inhibition of the neural noradrenalin reuptake and an enhanced release of serotonin.
      Tramadol has an antitussive action.
      Contrary to morphine, tramadol does not suppress respiration in analgesic doses over
      a large range.
      In addition gastrointestinal motility is less affected.
      Effects on the cardiovascular system tend to be minor.
      The potency of tramadol is reported to be 1/10 to 1/6 that of morphine.



5.2   Pharmacokinetic properties

      More than 90% of tramadol is absorbed after oral administration.


      The mean absolute bioavailability is approximately 70 %, irrespective of concomitant
      intake of food.


      The difference between absorbed and non-metabolised available tramadol is probably
      due to low first-pass effect. The first pass-effect after oral administration is a
      maximum of 30%.


      Tramadol has a high tissue affinity (V_d,β = 203 ± 40 l). Protein binding is about
      20%.


      It has been found that after administration of the 100mg Prolonged-release Tablets the
      maximum peak plasma concentration C_max 141 ± 40 ng/ml was reached after 4.9
      hours. After administration of the 200mg Prolonged-release Tablets a C_max of 260
      ± 62 ng/ml was reached after 4.8 hours.


      Tramadol passes the blood-brain and placental barrier. Very small amounts of the
      active substance and its O-demethyl derivative are found in the breast-milk (0.1% and
      0.02% respectively of the applied dose).


      Elimination of half-life t½β is approximately 6 h, irrespective of the mode of
      administration. In patients above 75 years of age it may be prolonged by a factor of
      1.4.
      In humans tramadol is mainly metabolised by means of N- and O-demethylation and
      conjugation of the O-demethylation products with glucuronic acid. The enzymes
      involved in the metabolism of tramadol are the cytochrome P450 isoenzymes,
      CYP3A4 and CYP2D6. Only O-desmethyltramadol is pharmacologically active.
      There are considerable inter-individual quantitative differences between the other
      metabolites. So far, eleven metabolites have been found in the urine. Animal
      experiments have shown that O-desmethyltramadol is more potent than the parent
      substance by the factor 2-4. Its half life t½β (6 healthy volunteers) is 7.9 h (range 5.4-
      9.6 h) and is approximately that of tramadol.


      The inhibition of one or both isoenzymes, CYP3A4 and CYP2D6 involved in the
      metabolism of tramadol, may affect the plasma concentration of tramadol or its active
      metabolite. The clinical consequences of any such interactions are not known.


      Tramadol and its metabolites are almost completely excreted via the kidneys.
      Cumulative urinary excretion is 90% of the total radioactivity of the administered
      dose. In cases of impaired hepatic or renal function the half-life may be slightly
      prolonged. In patients with cirrhosis of the liver, elimination half-lives of 13.3 ± 4.9 h
      (tramadol) and 18.5 ± 9.4 h (O-desmethyltramadol), in an extreme case 22.3 h and 36
      h respectively were found. In patients with renal insufficiency (creatinine clearance <
      5 ml/min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in an extreme case 19.5 h and
      43.2 h, respectively.


      Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.


      The relationship between serum concentrations and the analgesic effect is
      dosedependent, but varies considerably in isolated cases. A serum concentration of
      100 - 300 ng/ml is usually effective.



5.3   Preclinical safety data

      On repeated oral and parenteral administration of tramadol for 6 to 26 weeks to rats
      and dogs, and oral administration for 12 months in dogs, there was no evidence of
      changes caused by the active substance in haematogical, clinico-chemical or
      histological investigations.
      Central nervous manifestations only occurred after high doses considerably above the
      therapeutic range: restlessness, salivation, convulsions, and reduced weight gain.


      Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight
      respectively, and dogs rectal doses of 20 mg/kg body weight without any reactions.


      In rats tramadol dosages from 50 mg/kg/day upwards caused toxic effects in dams
      and raised neonate mortality. In the offspring retardation occurred in the form of
      ossification disorders and delayed vaginal and eye opening. The fertility of male rats
      was not influenced.


      After higher doses (from 50 mg/kg/day upwards) females exhibited a reduced
      pregnancy rate.


      In rabbits, toxic effects occurred as of 125 mg/kg in the mother and skeleton disorders
      in the young.


      In some in-vitro test systems there was evidence of mutagenic effects.


      In-vivo studies showed no such effects. According to knowledge gained so far,
      tramadol can be classified as non-mutagenic.


      Experiments have been performed on rats and mice with regard to the tumorigenic
      potential of tramadol.


      The study in rats showed no evidence of any substance-related increase in the
      incidence of tumours.


      In the study in mice there was an increased incidence of liver cell adenomas in male
      animals (a dose-dependent, non-significant increase from 15 mg/kg upwards) and an
      increase in pulmonary tumours in females of all dosage groups (significant, but not
      dose-dependent).


6     PHARMACEUTICAL PARTICULARS

6.1   List of excipients

      Hydroxypropylcellulose
      Calcium hydrogen phosphate dihydrate
      Colloidal anhydrous silica.
      Magnesium stearate
6.2   Incompatibilities

      Not applicable.

6.3   Shelf life

      3 years

6.4   Special precautions for storage

      Store in the original package in order to protect from light.

6.5   Nature and contents of container

      Cartons consisting of:
      Al – PVC / PVdC blisters
      Packs of 10, 20, 30, 50, 60, 100, 150 tablets.


      Tablet container consisting of: Polypropylene body and closure with aluminium
      tagger.
      Pack size: 100 tablets.
      Not all pack sizes may be marketed.



6.6   Special precautions for disposal

      No special requirements.



7     MARKETING AUTHORISATION HOLDER

      Brown & Burk UK Ltd
      5, Marryat Close
      Hounslow West
      Middlesex
      TW4 5DQ
      UK
8    MARKETING AUTHORISATION NUMBER(S)

     To be completed nationally.



9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE
     AUTHORISATION

     2011-04-28


10   DATE OF REVISION OF THE TEXT

     2011-04-28

				
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